Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II ß-Turn.

In an effort to target polypeptides at nonterminal sites, we screened the binding of the synthetic receptor cucurbit[8]uril (Q8) to a small library of tetrapeptides, each containing a nonterminal dipeptide binding site. The resulting leads were characterized in detail using a combination of isothermal titration calorimetry, 1H NMR spectroscopy, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. The equilibrium dissociation constant values determined for the binding of Q8 to nonterminal dipeptide sites Lys-Phe (KF) and Phe-Lys (FK) were 60 and 86 nm, respectively. These are to the best of our knowledge the highest affinities reported to date for any synthetic receptor targeting a nonterminal site on an unmodified peptide. A 0.79 Å resolution crystal structure was obtained for the complex of Q8 with the peptide Gly-Gly-Leu-Tyr-Gly-Gly-Gly (GGLYGGG) and reveals structural details of the pair-inclusion motif. The molecular basis for recognition is established to be the inclusion of the side chains of Leu and Tyr residues, as well as an extensive network of hydrogen bonds between the peptide backbone, the carbonyl oxygens of Q8, and proximal water molecules. In addition, the crystal structure reveals that Q8 induces a type II ß-turn. The sequence-selectivity, high affinity, reversibility, and detailed structural characterization of this system should facilitate the development of applications involving ligand-induced polypeptide folding.

Stereoelectronically-induced allosteric binding: shape complementarity promotes positive cooperativity in fullerene/buckybowl complexes.

A novel 2 : 1 host-guest complex forms between 8-tert-butyl-6b2-azapenta-benzo[bc,ef,hi,kl,no]corannulene (1) and C60 with positive cooperativity (α = 2.56) and high affinity (K1 × K2 = 2.8 × 106 M-2) at 25 °C. The C60 undergoes increasing shape complementarity toward 1 throughout the binding process.

Cyclic (Aryl)(Amido)Carbenes: NHCs with Triplet-like Reactivity.

The synthesis and study of a library of cyclic (aryl)(amido)carbenes (CArAmCs), which represent a class of electrophilic NHCs that feature low calculated singlet-triplet gaps (ΔEST =19.9 kcal mol-1 ; B3LYP/def2-TZVP) and exhibit reactivity profiles expected from triplet carbenes, are described. The electrophilic properties of the CArAmCs were quantified by analyzing their respective selenium adducts, which exhibited the largest downfield 77 Se NMR chemical shifts (up to 1645 ppm) measured for any NHC derivative known to date, as well as their Ir carbonyl complexes, from which large Tolman electronic parameter (TEP) values (up to 2064 cm-1 ) were ascertained. The CArAmCs were found to engage in reactions that are typically observed with triplet carbenes, including C-H insertions, [2+1] cycloadditions with alkenes as well as alkynes, and spontaneous oxidation upon exposure to oxygen.

Stereoelectronically Directed Photodegradation of Poly(adamantyl Vinyl Ketone).

Adamantyl vinyl ketone (AVK) and its copolymers are synthesized using reversible addition fragmentation chain-transfer (RAFT) methodology and then degraded using UV light. The polymerization of AVK is found to be controlled as indicated by a linear correlation between the molecular weights of the polymers produced and monomer conversion as well as a series of chain extensions. The RAFT method is also used to synthesize random and block copolymers of AVK and methyl methacrylate. Irradiating poly(adamantyl vinyl ketone) (PAVK) with UV light affords a polyolefin and adamantane as the major products. Similar products are obtained, along with poly(methyl methacrylate) (PMMA), when the block copolymer is subjected to UV light. The random copolymer undergoes complete degradation under similar conditions. A mechanism wherein stereoelectronic effects channel photodegradation through Norrish I Type pathways in a manner that preserves the main chain of the polymer during the decomposition process is proposed.

Burgess Reagent Facilitated Alcohol Oxidations in DMSO.

The Burgess reagent ([methoxycarbonylsulfamoyl]triethylammonium hydroxide) has historically found utility as a dehydrating agent. Herein we show that, in the presence of dimethyl sulfoxide, the Burgess reagent efficiently and rapidly facilitates the oxidation of a broad range of primary and secondary alcohols to their corresponding aldehydes and ketones in excellent yields and under mild conditions, and can be combined with other transformations (e.g., Wittig olefinations). A mechanism similar to those described for the Pfitzner-Moffatt and Swern oxidations is proposed.

Chemoselective N-deacetylation under mild conditions.

A mild and efficient chemoselective N-deacetylation using the Schwartz reagent at room temperature in rapid time is described. The mild and neutral conditions enable orthogonal N-deacetylation in the presence of some of the common protecting groups (viz. Boc, Fmoc, Cbz, Ts). The deprotection conditions did not induce any epimerization at the chiral amino centre.

Stereoselective approach to cis-2,3-disubstituted piperidines via reduction of N-acyliminium ion intermediate: enantioselective synthesis of (+)-(2S,3S)-CP-99,994.

A very simple and efficient stereoselective approach to cis-2,3-disubstituted piperidines via the reduction of N-acyliminium ion intermediates is described. Application of this methodology is exemplified by the enantioselective total synthesis of (+)-(2S,3S)-CP-99,994.